Fc-y gamma Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer

Geoffrey Liu, Dongsheng Tu, Marcia Lewis, Dangxiao Cheng, Leslie Sullivan, Zhuo Chen, Eric Morgan, John Simes, Timothy Price, Niall Tebbutt, Jeremy Shapiro, G Mark Jeffery, J. Daniel Mellor, Thomas Mikeska, Shakeel Virk, Lois Shepherd, Derek Jonker, Christopher O'Callaghan, John Zalcberg, Christos KarapetisAlexander Dobrovic

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    Purpose: Two germline Fc-g receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximabrelated outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR. Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism-treatment arm interaction term. Results: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype-treatment interaction for KRAS wild-type patients was observed for OS (P =0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab(vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A). Conclusions: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles.

    Original languageEnglish
    Pages (from-to)2435-2444
    Number of pages10
    JournalClinical Cancer Research
    Volume22
    Issue number10
    DOIs
    Publication statusPublished - 15 May 2016

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